The Role of Trigeminal Function in the Sensation of Nasal Obstruction in Chronic Rhinosinusitis

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1 The Laryngoscope VC 2016 The American Laryngological, Rhinological and Otological Society, Inc. The Role of Trigeminal Function in the Sensation of Nasal Obstruction in Chronic Rhinosinusitis Joe Saliba, MD; Naif Fnais, MD; Marcel Tomaszewski, MD; Junie S. Carriere, BA; Saul Frenkiel, MD; Johannes Frasnelli, MD; Marc A. Tewfik, MD, MSc Objectives/Hypothesis: Trigeminal sensation (TS) within the nasal cavity is important for the perception of nasal airflow. The objective of this study is to examine whether impaired TS contributes to the sensation of nasal obstruction in patients with chronic rhinosinusitis (CRS). Study Design: Prospective case-control study conducted in a tertiary referral rhinology clinic. Methods: Cases consisted of CRS patients with subjective nasal obstruction, not previously treated with oral corticoids. Controls consisted of patients without CRS. Neither group demonstrated obvious anatomical obstructions. Both groups underwent peak nasal inspiratory flows (PNIF), olfactory testing (quick eight-item odor identification test), and trigeminal testing (lateralization task using eucalyptol and odorless solvent). Results: A total of 28 subjects (14 CRS patients and 14 controls) were recruited. Analyses revealed no statistical differences in age (P 5.93), gender (P 5.47), or PNIF (P 5.82) between the two groups, but they differed in Lund-Mackay scores (P <.001). There was no significant difference in olfactory testing (P 5.15). CRS patients had significantly lower scores on trigeminal lateralization testing than controls (P 5.007). Linear regression revealed that Lund-Mackay scores contributed a significant amount of variance to trigeminal lateralization scores, controlling for age and sex (F , P 5.004, R ). Conclusions: This is the first study to demonstrate that patients with CRS have lower TS than healthy controls. Our results suggest defective TS could play a role in the sensation of nasal obstruction in CRS. Key Words: Trigeminal sensation, nasal obstruction, chronic rhinosinusitis, olfaction, inflammation. Level of Evidence: 3b. Laryngoscope, 126:E174 E178, 2016 INTRODUCTION Nasal obstruction is one of the main features of chronic rhinosinusitis (CRS). 1 Findings on physical examination, such as a diffuse nasal polyposis, a deviated nasal septum, or an edematous nasal mucosa, can explain the obstructive symptomatology in most CRS subjects. 2 However, otolaryngologists frequently encounter CRS patients presenting with subjective nasal obstruction, in whom From the Department of Otolaryngology Head and Neck Surgery (J.S., N.F., M.T., S.F., M.A.T), McGill University, Montreal, Quebec, Canada; Department of Otolaryngology Head and Neck Surgery (N.F.), King Saud University, Riyadh, Saudi Arabia; Research Chair for Chemosensory Neuroanatomy, Department of Anatomy (J.F.), University of Quebec in Trois-Rivières, Trois-Rivières, Quebec, Canada; Department of Psychology (J.S.C.), McGill University, Montreal, Quebec, Canada; Center for Advanced Research in Sleep Medicine (J.F.), Sacre-Coeur Hospital, Montreal, Quebec, Canada. Editor s Note: This Manuscript was accepted for publication February 5, Presented at the Canadian Society of Otolaryngology Head and Neck Surgery Annual Meeting, Winnipeg, Manitoba, Canada, June 9, This work was supported by the Department of Otolaryngology- Head and Neck Surgery research fund, McGill University, Montreal, Quebec, Canada. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Marc A. Tewfik, MD, Assistant Professor of Otolaryngology Head & Neck Surgery, McGill University Health Centre, 1001 Boulevard Decarie, Rm D , Montreal, QC H4A 3J1 Canada. marc.tewfik@mcgill.ca DOI: /lary E174 examination reveals no objective findings to account for this complaint. In these patients, we believe defective trigeminal sensitivity (TS) could contribute to the sensation of impaired nasal breathing. The TS of the nasal cavity is provided by the ophthalmic and maxillary branches of the trigeminal nerve. 3 Trigeminal free nerve endings are scattered throughout the nasal mucosa and relay sensations that are of somatosensory, such as touch and temperature, and chemosensory nature. 4 Chemosensory sensation provides feelings of burning, tingling, freshness or coolness, and is generally thought to be responsible for the sensation of airflow in the nasal cavity. 3,5,6 Zhao et al. have confirmed that trigeminally relayed mucosal heat loss is the underlying stimulus responsible for nasal patency. 7,8 Studies have also shown that stimulating the trigeminal receptors in the nose with menthol provides a feeling of free nose, without changes in nasal resistance Conversely, the inhibition of those receptors with local anesthesia simulates a loss of patency. 12,13 There is therefore a basis for believing that defective TS precludes the proper detection of nasal airflow during inspiration, and that this translates clinically into a sensation of nasal obstruction. Although previous reports have demonstrated lower trigeminal function in patients suffering from head trauma or upper respiratory tract infection, this concept has not been explored in CRS patients. 14,15 The objective of this study was to examine whether impaired TS contributes to the sensation of nasal obstruction in CRS patients.

2 MATERIALS AND METHODS Participants and Study Design A prospective case-control study was conducted at a tertiary rhinology referral clinic of the McGill University Health Center (Montreal, Canada). The experimental protocol was approved by the ethics review board of McGill University, and all subjects signed an informed consent form before participating in the study. Cases consisted of adult (18 65 years old) CRS patients with primary complaints of impaired nasal breathing but no obvious anatomical obstructions on physical examination or computed tomography scan. The diagnosis of CRS was established on the basis of symptoms and objective evidence of chronic inflammation on nasal endoscopy and/or imaging. 1 The CT scan was performed as part of routine care and was reviewed by a senior rhinologist. Only cases with a Lund- Mackay (LM) score between 4 and 20 were retained in this study. Subjects were excluded if they had a polyposis of grade 2 or more, underwent a previous functional endoscopic sinus surgery (FESS), or had received treatment with systemic corticoids in the month prior to testing. Patients referred to the rhinology clinic for a preoperative assessment of a skull base tumor were recruited as controls. None suffered from concomitant CRS or nasal obstruction. All subjects were assessed by anterior rhinoscopy and nasal endoscopy by a senior rhinologist prior to recruitment to confirm eligibility requirements. Participants were excluded if they suffered from conditions resulting in chemosensory dysfunction such as psychiatric disorders, traumatic brain injuries, neurodegenerative diseases, or recent acute upper respiratory tract infections. All participants were asked to rate their olfactory function and nasal patency using a 10-cm visual analogue scale. For olfactory function, the left-hand end of the scale indicated absent olfaction, whereas the right-hand end indicated excellent olfaction. Similarly, the left-hand end of the nasal patency scale was labeled with no patency, whereas the righthand end was labeled with complete patency. The peak nasal inspiratory flow (PNIF) was also determined prior to testing using a technique previously described in Berm uller et al. 16 In brief, a portable spirometer (In-Check Inspiratory Flow-Meter; Ferdinand Menzel Medizintechnik GmbH, Vienna, Austria) was employed with a face mask fit tightly around the subject s mouth and nose. Subjects were asked to perform a forced maximal inspiration, with their mouth closed, at the end of a maximal expiration that followed three medium deep breaths. The maneuver was repeated three times, and only the highest value was recorded. PNIF represents the highest airflow achieved through both nostrils during maximum forced nasal inspiration, and is an objective measure of airflow resistance in the nasal cavity. 16 All subjects then underwent testing for (1) olfactory function and (2) trigeminal function. Olfactory Testing Numerous reports have demonstrated an interaction between olfaction and TS in nasal chemoreception. 3 6 Binasal olfactory testing was therefore performed using a quick eightitem odor identification test. Subjects had to identify eight common odors (cola, pear, strawberry, rose, peach, lemon, almond, cinnamon) presented with tinted glass bottles (50 ml) each containing three cotton balls filled with 2.5 ml of a single pure odorant. All odorants were released immediately in front of the nostrils in a randomized sequence. Subjects were asked to identify each odor separately from a list of four items. Binasal olfactory sensitivity was quantified as the sum of correctly identified odors. Trigeminal Function Testing Trigeminal function was assessed using a previously reported experimental paradigm. 5,17 In brief, a lateralization task was used in which trigeminal activation was evaluated by the subject s ability to lateralize stimuli presented to either nasal cavity. Eucalyptol was chosen as a stimulus because it was shown to activate the trigeminal system, evoking a cooling sensation in the nose. 17 In each trial, the subjects were presented with two polyethylene bottles (volume 250 ml) equipped with custom made round caps with two openings. One bottle contained 15 ml of 50% eucalyptol solution dissolved in propylene glycol, and the other bottle contained odorless propylene glycol solvent only. Under blindfolded conditions, the subjects simultaneously moved the two bottles close to their nostrils so that the caps sealed the left and right nostrils. Subjects were instructed to take one sniff, so that the air from the left and right bottles reached into the left and right nostrils, respectively. After each trial, the subjects determined the localization, left or right, of the trigeminally mediated sensation (i.e., cooling sensation) by raising the corresponding hand. Task performance was calculated simply by adding up the number of correct localizations. A total of 40 stimuli were presented to the subjects. Stimulation of the nostrils followed a pseudorandomized sequence in which each nostril was stimulated 20 times. An interstimulus interval of exactly 30 seconds was used to avoid habituation, resulting in a total testing time of 20 minutes. Statistical Analyses Descriptive data for continuous variables were analyzed using Independent sample t tests. Correlational analyses were used to examine the associations between study variables (Table I). A t test for independent samples was also used to compare CRS patients to controls on all study variables. A linear regression was performed to examine the relation between LM scores and trigeminal lateralization scores. From a clinical perspective, scores below or equal to 20 all indicate chance performance and cannot be used to assess the severity of TS impairment between participants. Therefore, to adjust for by-chance level in analyses in which lateralization scores were computed individually as a continuous variable (correlations and linear regression), results on this task were floored to 20. Such manipulation was not performed in the group analyses (t test) in an effort to avoid introducing a bias in group means. Finally, individual performance on the trigeminal lateralization task was analyzed as a categorical variable (pass/fail), in which scores above 25 (out of 40) were regarded as significantly above chance level (i.e., pass) according to binomial distribution (P <.05). 18 v 2 analysis was then performed to compare pass rates between the study groups. The a level was set at.05. All analyses were performed using IBM SPSS statistics version 21.0 (IBM Corp., Armonk, NY). RESULTS A total of 14 CRS patients (mean age: 51.4 years) and 14 controls (mean age: 50.9 years) were recruited between 2013 and Group differences between CRS and controls on all study variables are presented in Table I. There were no significant differences in mean age or gender between CRS patients and controls. PNIF data also revealed no differences in nasal airflow resistance between our two study groups. As expected, LM scores were significantly higher in CRS patients (t , P <.001). Olfaction ratings on visual analogue scales did not differ significantly between CRS patients and controls (t , P 5.07). Binasal odor identification scores E175

3 TABLE I. Group Characteristics and Study Variables. Cases (n 5 14) Controls (n 5 14) t Test P Value Mean age (yr) Gender (% female) Mean PNIF (L/min) Mean Lund-Mackay scores <.001* Olfaction ratings on VAS (%) Nasal patency ratings on VAS (%) * *Statistical significance. PNIF 5 peak nasal inspiratory flow; VAS 5 visual analogue scale, were not significantly worse in CRS subjects (CRS, ; controls ; t 5 1.5, P 5.15) (Fig. 1), reflecting the subjective ratings described above. Olfactory function was not associated with age (r , N 5 28, P 5.39) or gender (t , P 5.15). Subjective nasal patency was significantly worse in CRS patients than controls on visual analog scales (t , P 5.001). Likewise, CRS patients were found to have significantly worse trigeminal lateralization scores than controls (CRS, ; controls, ; t 5 4.3, P <.001) (Fig. 2). CRS subjects also demonstrated significantly higher failure rates on the trigeminal lateralization task when analyzed according to binomial statistics (failures: CRS, 9/14; controls, 2/14; v , P 5.007). Subjective nasal patency scores in three of the five CRS patients who passed the lateralization task ranged between 5 and 7, the highest ratings among this subject group. Similarly, in the control group, the two subjects who failed the lateralization task demonstrated the poorest subjective patency ratings. Results also demonstrated a correlation between trigeminal and olfactory functions (r , N 5 28, P 5.01). On the other hand, trigeminal function was not associated with age (r , N 5 28, P 5.14) or gender (t 521.7, P 5.11). As expected, a strong negative correlation was found between LM and trigeminal lateralization scores (r , N 5 28, P <.001) (Fig. 3). Furthermore, a linear regression performed across all subjects revealed that LM scores contributed a significant amount of variance to trigeminal lateralization scores, controlling for age and gender (F , P 5.004, R ). DISCUSSION The present study is the first to report inferior trigeminal function in the nasal cavities of patients suffering from CRS. This finding confirms our hypothesis that impaired TS contributes to the subjective sensation of nasal obstruction in CRS patients. The pathophysiology underlying defective TS in CRS patients is an interesting topic that merits further investigation. It is well established that LM scores indicate the degree of inflammatory disease in CRS. 19 On the other hand, the results of this study demonstrate that LM scores also contributed a significant amount of variance to trigeminal lateralization scores. In light of such findings, one might postulate a relation between inflammation and TS. Although this hypothesis was not directly tested in our study, there is a basis for believing Fig. 1. Number of correctly identified odors in chronic rhinosinusitis patients and controls. Overall, binasal odor identification was not different between chronic rhinosinusitis (CRS) patients and controls (CRS, ; controls ; t 5 1.5, P 5.15). Fig. 2. Trigeminal lateralization scores in chronic rhinosinusitis (CRS) patients and healthy controls. CRS patients were found to have significantly worse mean trigeminal lateralization scores than controls (CRS, ; controls, ; t 5 4.3, P <.001). E176

4 Fig. 3. Relation between trigeminal lateralization scores and Lund- Mackay scores. Lateralization scores (floored to 20 [i.e., by-chance level]) were strongly correlated with Lund-Mackay scores (r , N 5 28, P <.001). it might be accurate. In recent years, the study of transient receptor potential (TRP) ion channels provided insight into nasal chemosensation. Reports have shown that function of TRPV1 receptors, involved in the trigeminally mediated heat-like effects of capsaicin, is modulated by inflammatory mediators released in the context of nerve injury or inflammation. 20 Likewise, the activity of the TRPA1 receptor, responsible for the trigeminally mediated pungent sensation associated with mustard oil, is also influenced by inflammatory markers such as prostaglandins and reactive oxygen species. 21 TRPM8, an ion channel related to TRPV1 and TRPA1, responds to both eucalyptol and cool air temperatures and is involved in airflow detection. 22,23 Although the molecules that mediate TRPM8 s activity in inflammatory states such as CRS remain elusive, it may be that reduction of this receptor s sensitivity to cold leads to impaired airflow detection. Accordingly, a rat model study by Linte et al. has shown decreased response to cooling in TRPM8-expressing neurons treated with bradykinin and prostaglandin E2. 24 Further studies are needed, however, to clarify such mechanisms in humans. To effectively study the role of TS on the sensation of impaired nasal breathing, it was important to remove the confounding effect of structural obstructions in the nasal cavity. This concept was the rationale behind our decision to recruit only CRS patients with subjective nasal obstruction but no radiologic or clinical evidence of objective obstacles to airflow. Three of the five CRS patients who passed the TS lateralization task (as well as both control subjects who failed this task) rated their obstruction as neutral. Although this reinforces our central hypothesis, it also highlights the importance of stringent inclusion criteria. Nonetheless, we believe our sample was adequately chosen to fulfill our study objectives. CRS patients rated their sensation of nasal obstruction to be significantly worse than controls, and both groups demonstrated similar mean PNIF measurements. In fact, mean PNIF recordings were within the normal range in both groups, demonstrating that nasal airflow was unimpeded. 16,25 This suggests that a process other than physical resistance to airflow in the nasal cavity was responsible for the subjective impression of nasal obstruction in our CRS patients. TS chemoreception was known to relay information about freshness and coolness within the nasal cavity, but Zhao and colleagues were the first to demonstrate that mucosal cooling was the mechanism driving the sensation of patency. 7 This cooling gradient resulted from a combination of conductive (related to air temperature) and evaporative (related to air humidity) heat loss. Computational fluid dynamics data from the same group further pointed toward a dynamic model of heat loss, in which mucosal cooling was modulated by an interaction between the inspired air s temperature and humidity and the individual s nasal airway passages. 8 Based on this model, it is possible that effective mucosal cooling in CRS patients is precluded by a restriction in the surface area available for heat exchange in the context of mucosal edema. The subjective nasal obstruction reported by CRS patients could therefore stem from a combination of defective TS and morphologic changes in the nasal airway resulting in altered air/mucosa interaction. Although the trigeminal system is generally responsible for nasal somatosensation and chemosensation, different areas of nasal mucosa exhibit varying sensitivities to trigeminal stimulation. Studies have previously shown that perception of chemosensory stimuli by the TS was most sensitive in the anterior portion of the nasal cavity, whereas the posterior nasal mucosa demonstrated heightened sensitivity to mechanical stimuli. 26,27 Such differences in the functional properties of the nasal mucosa reflect the distinct physiological roles of these areas. The posterior pharyngeal nose is involved in swallowing, and adequate detection of mechanical stimuli in this area is essential to prevent aspiration. On the other hand, the anterior part of the nasal cavity is key to nasal aerodynamics. 28 The nasal vestibule and internal nasal valve are anteriorly located in the nose. Collectively, these areas contribute the most to nasal airway resistance by forming a funnel through which must flow all the air reaching distal sections of the respiratory tract. 29 Once this funnel is passed, the inspired airflow is distributed primarily through the inferior and middle meatus, with a small fraction reaching the olfactory cleft. 30 A heightened sensitivity of the TS to chemosensory stimuli in this funnel is critical for the proper detection of the incoming nasal airflow during inspiration. In accordance with this model, Zhao and colleagues have demonstrated that the gradient of mucosal heat loss necessary for nasal patency sensation is not uniform throughout the nose, but rather concentrated in the nasal vestibule and valve regions. 7 There are a number of limitations to this study. First, in accordance with the literature, our study demonstrated a significant correlation between TS and olfactory function. 31,32 This relation between TS and olfaction could be a potential confounding source of TS performance in CRS, E177

5 because patients with CRS generally suffer from hyposmia or anosmia. 2,33 This is not applicable to our findings, however, as CRS patients performed equally to controls on olfactory identification testing. Second, the study sample size was limited. However, similar samples were employed in many studies examining TS and olfaction in a variety of patient populations and provided enough power to reveal significant results. 4,12,31,34 Lastly, due to the nature of the study, it was impossible to establish causal relations between lower TS score and other study variables such as LM scores, olfaction, and/or nasal obstruction ratings. However, LM scores contributed a significant amount of variance to trigeminal function lateralization scores, suggesting a possible role for inflammation in the pathophysiology of impaired TS in CRS. CONCLUSION This study is the first to demonstrate that patients with CRS have lower TS than controls. Our results suggest that an impaired TS could contribute to the sensation of nasal obstruction in CRS. To date, the pathophysiology underlying the defective TS in CRS patients is still unknown. Further studies are needed to examine the effect of chronic inflammation on trigeminal free nerve endings and nasal chemoreception. Other directions for future research include the study of intranasal corticoids and FESS therapies on TS outcomes in CRS patients. Acknowledgments The authors thank Benjhyna Daniel for her help in data collection. BIBLIOGRAPHY 1. Desrosiers M, Evans GA, Keith PK, et al. Canadian clinical practice guidelines for acute and chronic rhinosinusitis. J Otolaryngol Head Neck Surg 2011;40(suppl 2):S99 S Seiden AM, Duncan HJ. The diagnosis of a conductive olfactory loss. Laryngoscope 2001;111: Brand G. Olfactory/trigeminal interactions in nasal chemoreception. Neurosci Biobehav Rev 2006;30: Frasnelli J, Hummel T. Intranasal trigeminal thresholds in healthy subjects. 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